Psoriasis is a devastating autoimmune disease that manifests itself in the form of patchy inflammatory skin lesions that can appear anywhere throughout the body resulting in tremendous physical pain and discomfort. This chronic disease can also cause arthritic joints and have a profound impact on a patient?s psychological well- being. In psoriatic lesions, the detection of increased numbers of T cells and elevated levels of IL-17 and IFNg have implicated Th17 and Th1 cell subsets in disease pathogenesis. Interleukin-2 inducible T cell kinase (ITK) and TXK (also known as Resting Lymphocyte Kinase or RLK), are members of the Tec kinase family downstream of the T cell receptor and are involved in survival and activation of Th17 and Th1 cells, respectively. Selectively blocking ITK/TXK will result in a more broad inhibition of Th17 and Th1 cells as opposed to the mechanistic actions of approved clinical therapies which target either the upstream differentiator cytokines, IL-12/IL-23, or the effector cytokine IL-17, produced by activated Th17 cells. In this SBIR Phase 1 application, we propose to develop the first ITK/TXK inhibitor drug candidate for the treatment of psoriasis. We have developed an innovative kinase drug discovery platform (KINect) that exploits our proprietary kinase inhibitor library in the context of structure-based drug design (SBDD) to rapidly identify and develop active, drug-like chemical cores into drug candidates. Using this approach and our own ITK crystal structure we utilized our extensive drug development experience to identify a set of potent, selective, covalent and proprietary lead ITK/TXK inhibitor compounds that block Th17/Th1 cell activation. The advantage of our ITK/TXK inhibitor approach over that of ibrutinib (a pan-Tec kinase inhibitor used to treat B cell malignancies) is that we spare inhibition of the Tec family kinase member, Bruton?s tyrosine kinase (BTK), and avoid the associated increased risk of infection and bleeding. We propose to further develop ITK/TXK drug candidates to test the central hypothesis of this project that orally available inhibitors of ITK/TXK kinases will be effective immunotherapeutics that downregulate Th1 and Th17 activation in psoriatic lesions and demonstrate efficacy in psoriasis. The proposed research focuses on the following specific aims: (1) Identify ITK/TXK selective inhibitors with appropriate PK properties that modulate Th17 and Th1 cell activation and!(2) Determine efficacy of ITK/TXK selective inhibitors in pre-clinical in vivo models of T cell activation and psoriasis. SBIR Phase 1 studies will focus on generating preclinical in vivo efficacy data as well as pharmaceutical, pharmacokinetic and safety data, advancing the program to IND and initiation of human Phase 1 clinical evaluation in psoriasis patients. We anticipate a co-development partnership license following Phase 1/2 clinical studies with a deal value of >$200M. Given the need for new psoriasis therapies, the development of an effective ITK/TXK inhibitor drug will address a key unmet need and have a major medical impact.